1. Field of the Invention
The present invention relates to a process for micronizing a slightly-soluble drug. More specifically, it relates to a process for micronizing a slightly-soluble drug, which comprises grinding said drug in the presence of a sugar or sugar alcohol of a lower molecular weight as a grinding aid, and to a pharmaceutical formulation containing the resultant ultrafine drug as an active ingredient.
2. Description of the Related Arts
When a pharmaceutical formulation containing a drug is orally administered to subjects, a dissolution step is essential for the drug to be absorbed through gastrointestinal tract. It has long been recognized that a slightly-soluble drug often shows insufficient bioavailability because of the poor solubility in gastrointestinal fluids, which compels said drug to pass through the site of absorption before it completely dissolves in the fluids. Various attempts have been made from the aspect of pharmaceutics to improve and increase the absorption efficiency of a slightly-soluble drug in gastrointestinal tract.
Specific examples of said attempts employed for preparing improved formulations include following countermeasures.
1) Providing a soft gelatin capsule containing a solution of said drug in a nonaqueous solvent.
2) Providing a water-soluble salt of said drug.
3) Providing a solid solution which is prepared by dissolving the drug with a suitable polymer in an organic solvent and drying the solution promptly (see, reference 1 listed at the end of this specification).
4) A drug is dissolved in an organic solvent and adsorbed on a porous material in the form of ultrafine particles so that the surface area may be increased.
5) A drug is pulverized in the presence of an appropriate adduct to obtain an amorphous powder (see, references 3, 4 and 5).
6) A drug is just ground into a fine powder (see, reference 2).
The above countermeasures 1) to 5) are associated with alteration of properties of a drug in molecular level. These countermeasures, although advantageous in some aspects, have several disadvantages described below.
In the method of the above item 1), it is not always easy to find out a suitable nonaqueous solvent. In addition, the capsule size may become too big for oral administration. Furthermore, the production cost may be high.
The second method of the above item 2, where the drug is converted into a water-soluble salt, is not applicable to all kinds of drugs because many drugs may not form such salts. Additionally, formation of a water-soluble salt may be often accompanied by alteration of pharmaceutical activity of the drug and/or decrease its stability. Therefore, this method is just applicable to limited drugs.
The methods of the above items 3 and 4 are not applicable to every drug and the methods require the use of organic solvents which may be harmful to living bodies. Production cost may also be high in these methods.
In the method of the above item 5, a slightly-soluble drug is mixed with an adduct such as (1) .beta. -1,4-glucan, (2) adsorbent, or (3) polyvinylpyrrolidone. The drug is pulverized in the presence of such adduct to obtain the drug in the form of amorphous powder which may exhibit improved dissolution rate and bioavailability. However, the amorphous form is not physically stable and often converted reversibly to more stable crystal form. Consequently, the dispersion or dissolution properties of the drug may be changed as time passes.
The method of the above item 6) differs from those of items 1) to 5) which all change the properties of a drug in molecular level, in that the former contemplates to improve bioavailability of a drug through micronization. The micronization has the following advantages.
a) The alteration of crystal form of a drug is slight or moderate;
b) The operation is safe because no organic solvent is employed;
c) The production cost is low; and
d) The operation is easy.
In general, a milling process (it is also referred to as grinding, pulverization, and the like) is essential in the process of the production of pharmaceutical formulations. Examples of mills commonly used involve dry-type mills, such as jet, ball, vibration, and hammer mill. These dry-type mills are used to grind a drug alone to afford particles of several .mu.m in diameter. However, it is difficult to obtain finer particles by conventional means. Especially, preparation of submicron particles of less than 1 .mu.m in diameter is almost impossible.
This difficulty is associated with peculiar nature inherent to micronized particles that such particles have a tendency to aggregate, adhere, or solidify as the particle size decreases. Thus, it is extremely difficult to grind a drug into ultrafine particles having a diameter of less than several .mu.m by conventional milling procedures. Accordingly, a practically applicable process for preparing ultrafine particles of a drug has long been needed.